Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice

Recently it has been postulated that mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels rather than sarcolemmal K(ATP) (sarcK(ATP)) channels are important as end effectors and/or triggers of ischemic preconditioning (IPC). To define the pathophysiological significance of sarcK(ATP) channels, we conducted functional experiments using Kir6.2-deficient (KO) mice. Metabolic inhibition with glucose-free, dinitrophenol-containing solution activated sarcK(ATP) current and shortened the action potential duration in ventricular cells isolated from wild-type (WT) but not KO mice. MitoK(ATP) channel function was preserved in KO ventricular cells. In anesthetized mice, IPC reduced the infarct size in WT but not KO mice. Following global ischemia/reperfusion, the increase of left ventricular end-diastolic pressure during ischemia was more marked, and the recovery of contractile function was worse, in KO hearts than in WT hearts. Treatment with HMR1098, a sarcK(ATP) channel blocker, but not 5-hydroxydecanoate, a mitoK(ATP) channel blocker, produced a deterioration of contractile function in WT hearts comparable to that of KO hearts. These findings suggest that sarcKATP channels figures prominently in modulating ischemia/reperfusion injury in the mouse. The rapid heart rate of the mouse (>600 beats per minute) may magnify the relative importance of sarcK(ATP) channels during ischemia, prompting caution in the extrapolation of the conclusions to larger mammals

Acute effects of oestrogen on the guinea pig and human IKr channels and drug-induced prolongation of cardiac repolarization

Female gender is a risk factor for drug-induced arrhythmias associated with QT prolongation, which results mostly from blockade of the human ether-a-go-go-related gene (hERG) channel. Some clinical evidence suggests that oestrogen is a determinant of the gender-differences in drug-induced QT prolongation and baseline QTC intervals. Although the chronic effects of oestrogen have been studied, it remains unclear whether the gender differences are due entirely to transcriptional regulations through oestrogen receptors. We therefore investigated acute effects of the most bioactive oestrogen, 17β-oestradiol (E2) at its physiological concentrations on cardiac repolarization and drug-sensitivity of the hERG (IKr) channel in Langendorff-perfused guinea pig hearts, patch-clamped guinea pig cardiomyocytes and culture cells over-expressing hERG. We found that physiological concentrations of E2 partially suppressed IKr in a receptor-independent manner. E2-induced modification of voltage-dependence causes partial suppression of hERG currents. Mutagenesis studies showed that a common drug-binding residue at the inner pore cavity was critical for the effects of E2 on the hERG channel. Furthermore, E2 enhanced both hERG suppression and QTC prolongation by its blocker, E4031. The lack of effects of testosterone at its physiological concentrations on both of hERG currents and E4031-sensitivity of the hERG channel implicates the critical role of aromatic centroid present in E2 but not in testosterone. Our data indicate that E2 acutely affects the hERG channel gating and the E4031-induced QTC prolongation, and may provide a novel mechanism for the higher susceptibility to drug-induced arrhythmia in women

Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts

1. We investigated the effects of JTV-519 (4-[3-(4-benzylpiperidin-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride), a novel cardioprotective drug, on the repolarizing K(+) currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the effects of JTV-519 on experimental atrial fibrillation (AF) in isolated guinea-pig hearts. 2. In atrial cells stimulated at 0.2 Hz, JTV-519 in concentrations of 0.3 and 1 μM slightly prolonged the action potential duration (APD). The drug also reversed the action potential shortening induced by the muscarinic agonist carbachol in a concentration-dependent manner. 3. The muscarinic acetylcholine receptor-operated K(+) current (I(K.ACh)) was activated by the extracellular application of carbachol (1 μM), adenosine (10 μM) or by the intracellular loading of GTPγS (100 μM). JTV-519 inhibited the carbachol-, adenosine- and GTPγS-induced I(K.ACh) with the IC(50) values of 0.12, 2.29 and 2.42 μM, respectively, suggesting that the drug may inhibit I(K.ACh) mainly by blocking the muscarinic receptors. 4. JTV-519 (1 μM) inhibited the delayed rectifier K(+) current (I(K)). Electrophysiological analyses indicated that the drug preferentially inhibits I(Kr) (rapidly activating component) but not I(Ks) (slowly activating component). 5. In isolated hearts, perfusion of carbachol (1 μM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold (AFT). Addition of JTV-519 (1 μM) inhibited the induction of AF by prolonging MAP and ERP. 6. We conclude that JTV-519 can exert antiarrhythmic effects against AF by inhibiting repolarizing K(+) currents. The drug may be useful for the treatment of AF in patients with ischaemic heart disease

Inhibitory effects of aprindine on the delayed rectifier K(+) current and the muscarinic acetylcholine receptor-operated K(+) current in guinea-pig atrial cells

1. In order to clarify the mechanisms by which the class Ib antiarrhythmic drug aprindine shows efficacy against atrial fibrillation (AF), we examined the effects of the drug on the repolarizing K(+) currents in guinea-pig atrial cells by use of patch-clamp techniques. We also evaluated the effects of aprindine on experimental AF in isolated guinea-pig hearts. 2. Aprindine (3 μM) inhibited the delayed rectifier K(+) current (I(K)) with little influence on the inward rectifier K(+) current (I(K1)) or the Ca(2+) current. Electrophysiological analyses including the envelope of tails test revealed that aprindine preferentially inhibits I(Kr) (rapidly activating component) but not I(Ks) (slowly activating component). 3. The muscarinic acetylcholine receptor-operated K(+) current (I(K.ACh)) was activated by the extracellular application of carbachol (1 μM) or by the intracellular loading of GTPγS. Aprindine inhibited the carbachol- and GTPγS-induced I(K.ACh) with the IC(50) values of 0.4 and 2.5 μM, respectively. 4. In atrial cells stimulated at 0.2 Hz, aprindine (3 μM) per se prolonged the action potential duration (APD) by 50±4%. The drug also reversed the carbachol-induced action potential shortening in a concentration-dependent manner. 5. In isolated hearts, perfusion of carbachol (1 μM) shortened monophasic action potential (MAP) and effective refractory period (ERP), and lowered atrial fibrillation threshold. Addition of aprindine (3 μM) inhibited the induction of AF by prolonging MAP and ERP. 6. We conclude the efficacy of aprindine against AF may be at least in part explained by its inhibitory effects on I(Kr) and I(K.ACh)